The problem of making an active ingredient penetrate in the skin is of dramatic importance in cosmetics and, maybe even more, in dermatology. Natural penetration of most active ingredients, however, often has rates which may render the action of the active ingredient less effective or even fully ineffective. In order to overcome this, it is useful to find an agent which, by embedding in itself an active ingredient, causes it to penetrate in the skin at a greater rate than its natural rate, so that the effect is full and timely. Thereby, in many cases it would also be possible to reduce the concentration of active ingredient, thereby reducing to a minimum any possible side effects. In principle a delivery enhancement could also allow the use of active ingredients that otherwise have to be chemically transformed in order to be able to go through the stratum corneum. The problem with penetration improvement agents of this type is that they have to provide such acceleration, without interacting significantly with the active ingredient, so as not to invalidate the action thereof, nor damage the properties thereof.
One way might be the addition to the cosmetic product of small amounts of toxic substances, which, by killing some cells, would reduce penetration resistance. This way, however, risks damaging the skin irreversibly and is therefore to be avoided.
Also the application of moisturisers requires good skin penetration properties. Skin hydration and the variation thereof are often correlated with skin health and skin appearance. The lack of normal skin hydration is hence often associated with potentially serious cosmetic concerns and may cause distress and even skin disorders. There are two mechanisms of physiological modulation by the skin: 1) the natural humidifying factor and 2) the intercellular lipidic layers, located between keratinocytes. Said keratinocytes, being lipophilic, prevent excessive water evaporation through the epidermis. Although epidermal keratinocytes and the lipidic intercellular layers determine the barrier function of the skin, the lipidic compartment plays a predominant role. The normal physiological barrier function of the epidermis is hence based on highly regular laminae, into which intercellular lipids penetrate. As a matter of fact, in the epidermal stratum corneum, intercellular lipids are integrated in laminar gel phases and in laminar liquid crystals.
The most commonly used methods for modulating skin hydration consist in the topic application of emollients or humectants.
Emollients provide partial occlusion of the pores and may soften, humidify and improve the appearance of the stratum corneum of the skin.
On the other hand, humectants are generally hygroscopic molecules, such as for example urea or glycerol, capable of binding with atmospheric humidity, and they help keep skin water in balance.
Neither emollients nor humectants, however, affect the integrity of the barrier function of the skin.
In general, the skin lies on the surface of the body and serves as a sheath for the protection of inner organs, preventing them from coming into direct contact with the environment. In any case, the skin is extremely complex and has both intracrinous and paracrinous capabilities. Thus, the skin protects from UV radiation (melanogenesis), provides immune protection and has a barrier function which prevents the penetration of foreign particles. It is also dynamically involved in the management of the inner levels of water. It is also the seat of vitamin D photoproduction and of the distribution of vitamin E, introduced nutritionally.
The main skin layers are the dermis and the epidermis. The dermis is the site of the synthesis of the extracellular components, such as collagen, elastin and the glycosaminoglycans which are produced and secreted by the dispersed, resident fibroblastic cells. On the other hand, epidermal cell density is much higher and is represented predominantly by keratinocytes. The epidermis renews itself constantly through an outward flow and the differentiation of cells which originate from the epidermal stratum basale up to the stratum corneum (SC). The stratum corneum, the outermost layer of the epidermis, supplies most of the permeability barrier, which is mainly supplied by the organised embedding of keratinocytes into an extra-cellular matrix rich in lipids.
Chemical analyses have shown that the intercellular lipids of the stratum corneum consist mainly of ceramides, cholesterol, cholesterol esters and fatty acids, themselves being synthesised by keratinocytes. The three-dimensional organisation of those lipids has been the subject of various studies with the suggestion of various different models (Madison, 2003). In a recent model (Norlén, 2001), it has been suggested that the fats of the stratum corneum (mortar) exist in the form of a crystalline gel, arranged as multi-laminar system which is found among keratinocytes (bricks). A way to visualise the organisation of the lipids of the stratum corneum and the keratinocytes is to imagine a brick wall wherein the bricks representing keratinocytes are neatly juxtaposed and chelated in lipidic layers of mortar. The integrity of cell components is well-known and, in particular, the lipidic layers of the stratum corneum must necessarily maintain barrier function integrity. The destruction of the barrier function of the stratum corneum will lead to an increase of trans-epidermal water loss and to a consequent reduction in the level of skin hydration, with the negative consequences already illustrated above.
In addition to intercellular lipidic laminae (crystalline gel), other classes of lipids originating from sebum also play an important role in the stratum corneum. The primary lipids found in sebum are: cholesterol, sterol and wax esters, triglycerides and squalene (Stewart, 1992). Triglycerides can be produced inside the sebaceous gland and be released in the form of free fatty acids. Following the deposition in the outer surface of the stratum corneum, the sebum fats (or the surface lipids of the skin) perform an anti-microbic action (Georgel, 2005; Willie, 2003), as transient antioxidants (alfa-tocopherol) (Thiele, 1999), as well as supplying important molecules having targeted, biological purposes. For example, glycerol, more likely obtained by hydrolysis of triglycerides, acts as hygroscopic agent and participates in the capability of retaining the water of the stratum corneum (Fluhr, 2003). Some fatty acids, such as oleic acid and linoleic acid, behave as binders of peroxysome-proliferator-activated receptors (PPARs). It has been shown that the activation of PPARs is involved in keratocyte differentiation (Komuves, 2000) and in restoring the accelerated barrier function which follows acute abrogation of the barrier (Schurer, 2002; Mao Qiang, 2004). Despite being secreted on the outer surface of the stratum corneum, the sebum fats may be remarkably affected in maintaining the integrity of the lipidic configuration of much deeper layers. A number of studies have proved that, depending on the categories of lipids, a gradient of sebaceous surface lipids of the skin is detected through the stratum corneum (Blanc, 1989; Norlén, 1998; Sheu, 1999; Thiele, 1999; Norlén, 2001; Yagi, 2007).
The epidermal mission of keratinocytes ends with the desquamation process. Keratinocyte (or corneocyte) exfoliation is a process necessary for epidermal renewal and may be obtained through the proteolytic action of various enzymes (Houben, 2007). It is suggested that the desquamation phenomenon may cause a certain degree of structural dis-organisation in the intercellular, lipidic laminar matrix of the stratum corneum (Norlén, 2001, Sheu, 1999). The exfoliation process could be represented as a destabilising operation which opens small gaps in the underlying lipidic matrix (in the same way as the removal of a brick from a wall should crush the surrounding mortar). Such micropores may become paths for the sebaceous lipids to mix with the lipidic counterpart of the stratum corneum. Intermixing of sebaceous lipids with those features of inner layers of the stratum corneum might then occur. Together, these studies have established the physiological importance of sebum products in the skin surface as well as for the entire epidermis.
The object of the present invention is that of designing high-penetration dermatological agents which, on the one hand, allow faster penetration of the active ingredients into the skin and, on the other hand, act as biomimetic restructuring agents. The present invention is mainly based on fatty acid compositions similar to those found in the skin for generating skin-compatible liquid crystals, so as to mimike the molecular organisation of the intercellular lipidic laminae of the stratum corneum. The liquid crystals thus formed must have the opportunity to cross skin layers at high speed as well as to integrate physiologically in the lipidic barrier of the skin and to strengthen the integrity thereof.